- Lyme disease, which is caused by the tick-borne spirochete, Borrelia burgdorferi, is now the most common vector-borne infection in the United States. The broad range goal of this grant proposal is to understand the pathogenesis of chronic Lyme arthritis, a severe manifestation of the illness that may not respond to antibiotic therapy. In an effort to achieve this goal, the Lyme disease spirochete or its DNA or antigens will be sought in the joint fluid or synovium of patients with treatment-responsive or treatment-resistant Lyme arthritis. Since particular immune responses early in the infection correlate with the subsequent severity and duration of arthritis, specific immune factors will be determined both in patients with erythema migrans, the first sign of the infection, and in those with treatment-responsive or treatment-resistant arthritis, which occurs months to years after disease onset. These factors include 1) T and B cell reactivity with B. burgdorferi antigens, particularly to epitopes of outer-surface protein A (OspA), 2) the phenotype of T helper cells (Th1 or Th2) induced by spirochetal antigens, especially by OspA, and 3) the lymphokines and monokines present in erythema migrans or synovial lesions. The epitopes of OspA recognized, the cytokines produced, and the HLA-DR alleles of patients will be correlated with clinical findings in an effort to implicate particular immune responses in the pathogenesis of treatment-resistant arthritis. In addition to providing information about the pathogenesis and appropriate treatment of Lyme arthritis, these studies may give clues regarding the pathogenesis of other forms of chronic inflammatory arthritis in which the cause is not yet known, including rheumatoid arthritis.